Prostate cancer is the most frequently diagnosed non-cutaneous cancer, and is the second leading cause of cancer death in American men. It has been observed that elevated blood estrogen in the presence of high testosterone is an important risk factor that contributes to the prostate carcinogenesis. Dietary factors potentially linked to prostate cancer are numerous; however, an understanding of the mechanism(s) by which certain nutrients would protect the prostate from the genetic damage that is associated with tumor development remains unclear. The objectives of this application are to define the molecular mechanisms that link sex hormonal (estrogens/testosterone) stimulation to chronic inflammation, generation of reactive oxygen species (ROS) and uncontrolled prostate cell proliferation, and to evaluate the effectiveness of dietary strategies that target these processes. The central hypothesis of this application is that elevated estrogen, in the presence of high testosterone, causes prolonged activation of a redox-sensitive transcription factor, NFkappaB, through an estrogen receptor-mediated process. Prolonged NFkappaB activation initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative damage and signals for cell proliferation in the prostate. We further hypothesize that consumption of antioxidant-rich foods containing a combination of anti-estrogenic, anti-inflammatory and anti-proliferative components will be effective in reducing the prevalence of prostate cancer. The Aims of this project are: 1) to identify the molecular mechanisms by which exposure to elevated estrogen/testosterone causes chronic inflammation in prostate tissues of Noble rats, 2) to characterize the links of chronic inflammation leading to oxidative stress and proliferation signals in the prostate during sex hormone-induced prostate carcinogenesis, and 3) to evaluate the ability of novel whole food-based dietary modifications to prevent sex hormone-induced prostate carcinogenesis in Noble rats. The successful completion of our study is expected to reveal novel relationships among divergent factors involved in prostate cancer and aid in identifying key molecular targets for dietary intervention for prostate cancer prevention. Our 'whole food' based approach to cancer prevention is highly relevant to the development of evidence based and broadly applicable public health recommendations that will significantly reduce the burden of prostate cancer.